1. Field of the Invention
The present invention relates to novel diamide compounds and medicines useful in preventing and treating allergic immunological diseases, comprising such a compound as an active ingredient.
2. Description of the Background
IgE, which is a kind of immunoglobulin (Ig), is an allergen-specific molecule produced by an IgE producing cell differentiated from a B cell. This process is triggered by the contact of an immunocyte with an allergen in vivo.
IgE is produced in a target organ for an allergy and binds to a receptor on the surface of a mast cell, which is a central effector cell in an allergic reaction, or a basophil (sensitized state). After the sensitization, allergic chemical mediators such as histamine, leukotrienes, prostaglandins and PAF, and injuring enzymes such as tryptase are released from the mast cell stimulated by the reaction of the specific IgE and the allergen which invades in the living body, so that immediate responses, such as vascular permeability acceleration, smooth muscle constriction, and vasodilation are elicited. Further, cytokines such as IL-4, which directly activate other immune system cells, are also secreted from the stimulated mast cell. As a result, eosinophils, basophils and the like infiltrate into a tissue, and the allergic chemical mediators and tissue injuring proteins such as MBP, which are secreted by these inflammatory cells, induce a late response, so that the allergic symptom is lingered and taken seriously ill.
From this, IgE is considered a substance fundamentally participating in the attack of an allergic immunological disease.
Therefore, several compounds having an inhibitory effect on the production of an IgE antibody have heretofore been found and reported with a view toward developing antiallergic agents [Pharmacology and Therapy, 1994, 22(3), 1369; Japanese Patent Application Laid-Open No. 106818/1989; Japanese Patent Publication No. 17506/1995; and Japanese Patent Application Laid-Open No. 92216/1996]. However, the object has been not always sufficiently achieved under the circumstances.
Accordingly, it is an object of the present invention to find a compound having a strong inhibitory effect on the production of an IgE antibody so as to provide a medicine effective for allergic immunological diseases, comprising this compound as an active ingredient.
With the foregoing circumstances in view, the present inventors have carried out an extensive investigation. As a result, it has been found that novel diamide compounds represented by the general formula (1), which will be described subsequently, salts thereof, or solvates thereof have an excellent inhibitory effect on the production of an IgE antibody and are useful as prophylactic and therapeutic agents for various allergic immunological diseases, thus leading to completion of the present invention.
According to the present invention, there is thus provided a compound represented by the following general formula (1): 
wherein A is a phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl group which may be substituted;
X is a lower alkylene group which may be substituted; a divalent residue of an alicyclic compound which may be substituted, an aromatic compound which may be substituted, or a heterocyclic compound which may be substituted; an imino group which may be substituted; or a sulfur atom or an oxygen atom;
Y is a single bond or a lower alkylene group;
Z is a group of xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94(CHxe2x95x90CH)2xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94Cxe2x89xa1Cxe2x80x94, or a divalent residue of benzene, pyridine, pyrimidine or pyrazine which may be substituted; and
R is a hydrogen atom, or a lower alkyl, cycloalkyl, aryl or aralkyl group, with the proviso that A is not a phenyl group, a 4-chlorophenyl group nor a 4-methoxyphenyl group when X is an ethylene group, Y is a single bond, Z is xe2x80x94Cxe2x89xa1Cxe2x80x94, and R is a hydrogen atom; A is not a 3,4-dichlorophenyl group when X is a trimethylene group, Y is a single bond, Z is xe2x80x94(CHxe2x95x90CH)2xe2x80x94, and R is a hydrogen atom; and A is not a 3,4-dihydroxyphenyl group, a 3-hydroxy-4-methoxyphenyl group, a 3-methoxy-4-hydroxyphenyl group nor a 3,4-dimethoxyphenyl group when X is a tetramethylene group, Y is a single bond, Z is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94(CHxe2x95x90CH)2xe2x80x94, and R is a hydrogen atom, a salt thereof, or a solvate thereof.
According to the present invention, there is also provided a medicine comprising the above compound as an active ingredient.
According to the present invention, there is further provided a medicinal composition comprising the above compound and a pharmaceutically acceptable carrier.
According to the present invention, there is still further provided use of the above compound for a medicine.
According to the present invention, there is yet still further provided a method of treating an allergic immunological disease, which comprises administering an effective amount of the above compound.
The diamide compounds according to the present invention are represented by the general formula (1). As compounds similar to these compounds, 5-phenyl-2,4-pentadiene derivatives are described in J. Med. Chem., 1968, 11, 1073. However, these compounds are described only as antimalarial drugs, not as antiallergic agents. Japanese Patent Application Laid-Open No. 214766/1985 also describes compounds similar to the compounds (1) according to the present invention. However, the publication describes these compounds as 5-lipoxygenase inhibitors, but does not describe anything about the fact that they have an inhibitory effect on the production of an IgE antibody.
In the present invention, xe2x80x9calkylxe2x80x9d in alkyl groups, alkylamino groups, dialkylamino groups and the like means linear or branched alkyl generally having 1-12 carbon atoms, and lower alkyl groups are preferred. The lower alkyl groups include linear or branched alkyl groups having 1-8 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl groups. Of these, those having 1-6 carbon atoms, for example, methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl and n-hexyl groups, are particularly preferred.
xe2x80x9cAlkoxyxe2x80x9d in alkoxy groups, alkoxycarbonyl groups and the like means linear or branched alkoxy generally having 1-12 carbon atoms, and lower alkoxy groups are preferred. The lower alkoxy groups include linear or branched alkoxy groups having 1-8 carbon atoms. Specific examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy groups. Of these alkoxy groups, those having 1-6 carbon atoms are preferred.
Lower alkylene groups include linear or branched alkylene groups having 1-8 carbon atoms. Specific examples thereof include methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene and octamethylene groups.
Alicyclic compounds include saturated alicyclic hydrocarbons having 3-8 carbon atoms, for example, cycloalkanes such as cyclopentane, cyclohexane, cycloheptane and cyclooctane.
Aromatic compounds include aromatic compounds having 6-14 carbon atoms, such as benzene and naphthalene.
Heterocyclic compounds include 5- to 7-membered heterocyclic compounds containing 1-3 nitrogen atoms, such as pyrrolidine, pyridine, piperidine, piperazine and homopiperazine.
Cycloalkyl groups include cycloalkyl groups having 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
Aryl groups include aromatic groups having 6-14 carbon atoms, such as phenyl and naphthyl groups. Aralkyl groups include C6-14-aryl-C1-8-alkyl groups such as benzyl, phenylethyl and naphthylmethyl groups.
Alkylthio groups include alkylthio groups having 1-8 carbon atoms.
Halogen atoms include fluorine, chlorine, bromine and iodine atoms.
In the formula (1), A is a phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl group. These groups may have 1-3 substituents. Here, examples of the substituents on these groups include a hydroxyl group, halogen atoms, lower alkyl groups which may be substituted by 1-3 halogen atoms, lower alkoxy groups, an amino group which may be substituted by one or two lower alkyl groups, and alkylthio groups. As A, a phenyl group substituted by 1-3 substituents selected from among lower alkyl groups and lower alkoxy groups is particularly preferred.
The lower alkylene group represented by X is preferably a linear or branched alkylene group having 1-8 carbon atoms. A linear alkylene group having 5-8 carbon atoms is more preferred, with a hexamethylene group being particularly preferred. It is also preferred that X be an ethylene group. These groups may have a substituent such as a halogen atom, or a hydroxyl, lower alkoxy, carboxyl or lower alkoxycarbonyl group. Of these, a lower alkylene group which may be substituted by a carboxyl or lower alkoxycarbonyl group is particularly preferred.
The divalent residue of the alicyclic compound, which is represented by X, is preferably a divalent residue of a cycloalkane having 5-8 carbon atoms. Examples of the divalent residue of the aromatic compound, which is represented by X, include phenylene and naphthylene groups, with a phenylene group being particularly preferred. Here, the phenylene group may be any of 1,2-phenylene, 1,3-phenylene and 1,4-phenylene groups, with a 1,2-phenylene or 1,4-phenylene group being particularly preferred. Preferable examples of the divalent residue of the heterocyclic compound, which is represented by X, include divalent residues of pyridine, pyrrolidine, piperidine, piperazine, homopiperazine and the like. The divalent residue of the alicyclic compound, aromatic compound or heterocyclic compound, or the imino group, which is represented by X, may be substituted by a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted by a primary, secondary or tertiary amino group, a lower alkoxy group, a carboxyl group, a lower alkoxy-carbonyl group, an amino group, an alkylamino group, a dialkylamino group, a nitro group, a cyano group, an aralkyl group, or the like. Here, examples of the primary, secondary or tertiary amino group include amino, lower alkylamino and di-lower alkylamino groups.
X is preferably the divalent residue of the alicyclic compound which may be substituted, the divalent residue of the aromatic compound which may be substituted, or the divalent residue of the heterocyclic compound which may be substituted.
The lower alkylene group represented by Y is preferably a linear or branched alkylene group having 1-8 carbon atoms.
Examples of groups which may be substituted on the divalent residue of benzene, pyridine, pyrimidine or pyrazine represented by Z include halogen atoms, and lower alkyl, lower alkoxy, amino and nitro groups.
R is preferably a hydrogen atom, or a lower alkyl, cycloalkyl, phenyl or aralkyl group, with a hydrogen atom, a lower alkyl group, a cycloalkyl group having 5-8 carbon atoms, a phenyl group, a benzyl group or a phenylethyl group being particularly preferred.
In the formula (1), A is not a phenyl group, a 4-chlorophenyl group nor a 4-methoxyphenyl group when X is an ethylene group, Y is a single bond, Z is xe2x80x94Cxe2x89xa1Cxe2x80x94, and R is a hydrogen atom. Also, A is not a 3,4-dichlorophenyl group when X is a trimethylene group, Y is a single bond, Z is xe2x80x94(CHxe2x95x90CH)2xe2x80x94, and R is a hydrogen atoms. Further, A is not a 3,4-dihydroxyphenyl group, a 3-hydroxy-4-methoxyphenyl group, a 3-methoxy-4-hydroxyphenyl group nor a 3,4-di-methoxyphenyl group when X is a tetramethylene group, Y is a single bond, Z is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94(CHxe2x95x90CH)2xe2x80x94, and R is a hydrogen atom.
Among the above-described compounds, compounds obtained in Examples 3, 5, 13, 15, 22, 26, 29, 48, 49, 51, 55 and 57, which will be described subsequently, are particularly preferred in the present invention.
No particular limitation is imposed on the salts of the diamide compounds (1) according to the present invention so far as they are pharmaceutically acceptable salts. In the case where the diamide compounds (1) are basic compounds, however, examples of the salts include mineral acid salts such as hydrochlorides and sulfates; organic acid salts such as methanesulfonates, acetates, oxalates and citrates. In the case where the diamide compounds (1) are acidic compounds on the other hand, examples of the salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and organic basic salts such as pyridine salts, picoline salts and triethylamine salts.
The diamide compounds (1) may be present in the form of solvates such as hydrates.
The diamide compounds (1) can be prepared according to, for example, the following reaction formula: 
wherein A, X, Y, Z and R have the same meanings as defined above.
More specifically, the compounds (1) according to the present invention are obtained by the N-acylating reaction of a carboxylic acid (2) with a diamine (3).
The N-acylating reaction may be conducted by using any N-acylating reaction known per se in the art. It is particularly preferable to apply, for example, (a) a method in which the carboxylic acid (2) and the diamine (3) are reacted in the presence of a condensation reagent, preferably, a base and a condensation reagent in a solvent, or (b) a method in which a reactive derivative of the carboxylic acid (2) and the diamine (3) are reacted in a solvent.
Examples of the solvents used in these reactions may include dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, methylene chloride and dichloroethane. As the base, may be used an organic base such as pyridine, triethylamine or diisopropylethylamine, or an inorganic base such as sodium carbonate or sodium hydrogencarbonate. Examples of usable condensation agents include 1,3-dicyclohexylcarbodiimide, 1-cyclohexyl-3-morpholinoethyl-carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1,1xe2x80x2-carbonyldiimidazole, diethyl phosphorocyanidate, diphenylphosphoryl azide, bis(2-oxo-3-oxazolidinyl)-phosphinic chloride and 2-chloro-1-methylpyridinium iodide. Examples of usable derivatives of the carboxylic acid Include acid halides such as acid chlorides, acid azides, symmetric acid anhydrides, mixed anhydrides with pivalic acid or the like, and active esters such as cyanomethyl esters and p-nitrophenyl esters.
In each of the method (a) and the method (b), the N-acylating reaction is completed by reacting the carboxylic acid (2) with the diamine (3) at a reaction temperature of 0xc2x0 C. to 100xc2x0 C. for 30 minutes to 30 hours. The isolation and purification of the compound (1) from the reaction mixture may be conducted by using any methods known per se in the art, for example, filtration, extraction, washing, drying, concentration, recrystallization and various kinds of chromatography.
The compound (1) thus obtained may be converted into an acid-addition salt or a basic salt in a method known per se in the art.
The compound may also be converted into a solvate with a solvent for recrystallization, or the like, in particular, a hydrate.
Since the diamide compounds (1) according to the present invention have an excellent inhibitory effect on the production of an IgE antibody as demonstrated in Examples, which will be described subsequently, they are useful as medicines for prevention and treatment of various allergic immunological diseases, in which IgE participates, for example, asthma, atopic dermatitis, allergic rhinitis, inflammatory large bowel diseases, contact dermatitis and allergic ophthalmopathy.
The diamide compounds (1) or the salts thereof according to the present invention can be formulated into various oral and parenteral preparations in the form of a solid, semisolid or liquid by adding a pharmaceutically acceptable, inorganic or organic carrier in accordance with a method known per se in the art.
Examples of the oral preparations include tablets, pills, granules, soft and hard capsules, powders, grains, triturations, emulsions, syrups, pellets and elixirs. Examples of the parenteral preparations include injections, drops, infusions, ointments, lotions, tonics, sprays, suspensions, oils, emulsions, suppositories and eye drops. The active ingredients according to the present invention may be formulated into various preparations in accordance with a method known per se in the art. In these preparations, may be suitably used surfactants, excipients, colorants, smell corrigents, preservatives, stabilizers, buffers, suspension stabilizers, isotonic agents and the like, as needed.
The dose of the diamide compound (1) or the salt thereof varies according to the kind of the compound, the kind of a disease to be treated or prevented, an administration method, the condition, age, sex, weight of a patient to be administered, treatment time, and the like. However, the compound may be administered in a dose of 0.01-1,000 mg/kg of weight/day. The compound may be administered at once or in several portions, for example, 2 to 6 portions a day.